Increased epigenetic age in normal breast tissue from luminal breast cancer patients
Increased epigenetic age in normal breast tissue from luminal breast cancer patients
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DOI：
10.1186/s13148-018-0534-8
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发表时间：
2018-08-29
影响因子：
5.7
通讯作者：
Pusztai, Lajos
中科院分区：
文献类型：
--
作者：
Hofstatter, Erin W.;Horvath, Steve;Pusztai, Lajos
背景：年龄是乳腺癌发生的最重要的危险因素之一。然而，可能导致乳腺癌的正常乳腺组织中与年龄相关的变化尚不完全清楚。量化组织水平的DNA甲基化有助于理解这些过程。我们假设乳腺癌的发生可能与正常乳腺组织表观遗传老化加速有关。结果：88名受试者获得96份正常乳腺组织样本(乳腺癌=35名受试者/40名样本，未受影响的受试者=53名受试者/53名样本)。乳腺癌患者的正常组织标本来自初次乳腺癌切除标本的远端非肿瘤部位，而未受影响的女性标本来自Komen组织库(n=25)和非癌相关乳房手术标本(n=28)。患者被进一步分成四组：50岁患有乳腺癌和50岁不患有乳腺癌，50岁患有和不患有乳腺癌。使用Illumina Human Megylation450k珠芯片微阵列从提取的DNA样本中生成甲基化图谱。使用“表观遗传时钟”对数据进行分析，“表观遗传时钟”是一种已发表的衰老生物标记物，基于人类基因组中一组定义的353个CPG。由此得出的年龄估计，DNA甲基化年龄与实际年龄和乳腺癌状况有关。正常乳腺组织的DNA平均年龄与实际年龄有很强的相关性(r=0.712，p<；0.001)。与未受影响的同龄人相比，乳腺癌患者的正常乳腺组织显示出显著的年龄加速(p=0.002)。多变量分析显示，在调整了临床和人口统计学变量后，癌症患者正常乳腺组织中的表观遗传年龄加速仍然显著。此外，在正常乳腺组织中，吸烟与表观遗传年龄呈正相关(p=0.012)。结论：腔型乳腺癌患者在正常邻近乳腺组织中表现出显著的表观遗传年龄加速，这与在恶性乳腺组织中的类似发现一致。吸烟也与正常乳房组织的表观遗传年龄加速有关。需要进一步的研究来确定正常乳腺组织中的表观遗传年龄加速是否预测乳腺癌的发生，以及这是否在乳腺癌风险的时序年龄风险中起中介作用。
Background: Age is one of the most important risk factors for developing breast cancer. However, age-related changes in normal breast tissue that potentially lead to breast cancer are incompletely understood. Quantifying tissue-level DNA methylation can contribute to understanding these processes. We hypothesized that occurrence of breast cancer should be associated with an acceleration of epigenetic aging in normal breast tissue.Results: Ninety-six normal breast tissue samples were obtained from 88 subjects (breast cancer = 35 subjects/40 samples, unaffected = 53 subjects/53 samples). Normal tissue samples from breast cancer patients were obtained from distant non-tumor sites of primary mastectomy specimens, while samples from unaffected women were obtained from the Komen Tissue Bank (n = 25) and from non-cancer-related breast surgery specimens (n = 28). Patients were further stratified into four cohorts: age < 50 years with and without breast cancer and age >= 50 with and without breast cancer. The Illumina HumanMethylation450k BeadChip microarray was used to generate methylation profiles from extracted DNA samples. Data was analyzed using the "Epigenetic Clock," a published biomarker of aging based on a defined set of 353 CpGs in the human genome. The resulting age estimate, DNA methylation age, was related to chronological age and to breast cancer status.The DNAmAge of normal breast tissue was strongly correlated with chronological age (r = 0.712, p < 0.001). Compared to unaffected peers, breast cancer patients exhibited significant age acceleration in their normal breast tissue (p = 0.002). Multivariate analysis revealed that epigenetic age acceleration in the normal breast tissue of subjects with cancer remained significant after adjusting for clinical and demographic variables. Additionally, smoking was found to be positively correlated with epigenetic aging in normal breast tissue (p = 0.012).Conclusions: Women with luminal breast cancer exhibit significant epigenetic age acceleration in normal adjacent breast tissue, which is consistent with an analogous finding in malignant breast tissue. Smoking is also associated with epigenetic age acceleration in normal breast tissue. Further studies are needed to determine whether epigenetic age acceleration in normal breast tissue is predictive of incident breast cancer and whether this mediates the risk of chronological age on breast cancer risk.